Bipolar Disorder is a common, often severe mental illness. Family, twin, and adoption studies have demonstrated that genes are the major determinant of individual risk for the disorder, but as in other common disorders, the identification of these genes has proven to be a significant challenge. In collaboration with 10 academic centers across the United States, we have recruited a large sample of families in which at least 2 siblings suffer from bipolar disorder or related mood disorders. This is the largest sample ever to participate in a genetic study of bipolar disorder. All research participants have undergone a diagnostic interview and provided a blood sample for DNA analysis. Genetic linkage studies have been performed using molecular markers evenly spaced across all chromosomes. These studies suggest that regions on chromosomes 8, 6, 13, 17, 18, and 22, among others, may contain genes that contribute to bipolar disorder in these families. Ongoing work is aimed at identifying the actual genes involved. Single nucleotide polymorphisms are being used to identify small chromosomal regions that are overrepresented in people with bipolar disorder. This work has so far identified genes on chromosomes 13, 22, and 18 as the sites of genetic variation that increase risk for bipolar disorder in some people. Related collaborative projects are aimed at investigating genetic variation in candidate genes important in the stress response or regulation of mood or anxiety that may mediate risk for mood and anxiety disorders. In the past year, we have obtained additional evidence supporting association between genes on chromosomes 13 and 22 with risk for bipolar disorder. We have also identified genetic variation in the gene TPH2 that is associated both with bipolar disorder and with suicidal behavior.